Agitation in Alzheimers Disease A Regulatory Viewpoint Valentina - - PowerPoint PPT Presentation

Valentina Mantua, M.D., Ph.D.

CNSWP , SAWP Member, European Medicine Agency, London – UK CNS Assessor – Italian Medicines Agency (AIFA) – Rome –IT

Agitation in Alzheimer’s Disease A Regulatory Viewpoint

Public Declaration of transparency/interests*

Note: For this talk, I am not receiving any compensation * Valentina Mantua, in accordance with the updated policy on Conflict of Interest Regulations approved by AIFA Board of Directors (25.03.2015) and published

• n the Official Journal of 15.05.2015 according to 0044 EMA/513078/2010 on the handling of the conflicts of interest for scientific committee members and

experts

I nterests in pharmaceutical industry NO Currently Last 2 years More than 2 years but less than 5 years ago

Direct interests:

Employment with a company x Consultancy for a company x Strategic advisory role for a company x Financial interests x Ownership of a patent x

I ndirect interests:

Principal investigator x Investigator x Individual’s Institution/Organisation receives a grant or other funding x

The New Guidelines

• Discussion Paper Oct 2014
• EMA workshop Nov 2014
• Scientific advices EMA
• Scientific Advice-HTA Parallel
• Literature
• EMA Data Sharing Initiative
• FDA Guidelines March 2015
• Overview of comments Jul 2016

Indications

• Agitation in the context of AD is highly prevalent
• Currently only Risperidone is licensed for short-term (6 weeks)

treatment of persistent aggression

• Antipsychotics are commonly used for the treatment of

agitation in AD, despite the safety warning

• Citalopram is also often prescribed in off-label setting
• There is a high unmet need for the treatment of agitation
• Treatment of Agitation in AD is a valid development goal

Clinical Trials Features

• Double blind placebo controlled trial
• Rating scales such as NPI/NPI-C or CMAI have been endorsed

by regulatory authorities in registrational programs

• Cognition and function as secondary endpoints (detrimental

effect on cognition?)

• Duration 8-12 weeks
• Long term data on maintenance of efficacy,

rebound/discontinuation phenomena and safety

Challenges

• Heterogeneous definition/phenomenology of agitation
• Agitation has to be persistent / the duration of TX effect too!
• Medicines are investigated in a complex setting (multiple

pharmacological/non-pharmacological interventions)

• Placebo response
• Statistical models should account for intercurrent events

(specify handling of missing data and target estimation)

• Safety (falls, detriment cognition, QTc prolungation)